Abstract Transient receptor potential cation channel, subfamily V, member 3 (TRPV3) channel was identified as a molecular sensor of “warm to hot” temperatures almost a decade ago (Xu et al., 2002; Smith et al., 2002; Peier et al., 2002 [ [1] , [2] , [3] ]). Subsequently, based on its neuronal up-regulation in pain states, it was recognized as a promising target in novel analgesic development (Facer et al., 2007; Bevan et al., 2008 [ 10 , 40 ]). TRPV3 channel has been under continued research since then, albeit not as aggressively as few other TRP channels. Nevertheless, learning from the recent efforts has further revealed its intriguing role in hair and skin homeostasis, cutaneous sensory responses, and potential role in skin diseases. Recent recognition of its gain-of-function mutation in mice and humans clearly takes the scope of TRPV3 blockade beyond pain sensory pathways to attenuating hyperkeratotic, inflammatory skin disorders accompanied with itch and/or pain (Imura et al., 2009; Yoshika et al., 2009; Lin et al., 2009 [ [33] , [34] , [35] ]). This chapter gives recent insights into the therapeutic potential of TRPV3 blockade in multiple diseases with unmet medical needs including chronic pain conditions and skin diseases.